Prostate-specific antigen (PSA) is widely used for monitoring treatment response and disease progression in patients with prostate cancer.¹ While previous studies have shown that lower PSA concentrations during hormone-based therapy are associated with improved survival outcomes, the prognostic value of on-treatment PSA in patients with metastatic and very high-risk nonmetastatic prostate cancer receiving contemporary treatment strategies are less defined.² Findings from a post hoc analysis of the STAMPEDE platform trial demonstrated that lower PSA levels during treatment, particularly ≤0.2ng/mL, were strongly associated with improved long-term overall survival (OS), although disease burden continued to influence outcomes even among patients achieving deep PSA responses.²

The STAMPEDE platform trial has previously demonstrated significant survival benefits with treatment intensification through the addition of abiraterone, enzalutamide, docetaxel, or prostate radiotherapy to androgen deprivation therapy (ADT) in selected patients with advanced prostate cancer.³ Although PSA is routinely used to assess treatment response, the prognostic significance of specific on-treatment PSA thresholds in patients receiving these contemporary treatment intensification strategies remains unclear, particularly in those with very high-risk nonmetastatic disease.² To address this knowledge gap, a post hoc analysis was conducted to evaluate the association between on-treatment PSA levels and long-term survival outcomes in patients with metastatic and very high-risk nonmetastatic prostate cancer.²

The post hoc analysis included 7,129 patients with metastatic or very high-risk nonmetastatic prostate adenocarcinoma enrolled across five randomized phase 3 STAMPEDE trials conducted at 126 hospitals and oncology centers in the United Kingdom and Switzerland between 2005 and 2016.² Overall, 62% of patients had metastatic disease and 38% had very high-risk nonmetastatic disease.² Patients were randomly assigned to receive standard of care (ADT ± docetaxel) or one of five experimental treatment strategies, including ADT + docetaxel ± zoledronic acid, ADT + abiraterone acetate ± enzalutamide, or ADT + prostate radiotherapy in selected patients with metastatic disease.² Landmark analyses evaluated the association between PSA concentrations at 6, 12, and 24 weeks after randomization and OS, with a median follow-up of 9.6 years.²

Although PSA measured at 24 weeks was most strongly associated with OS, achieving a PSA level of ≤0.2ng/mL at any assessed time point predicted favorable long-term outcomes.² Among patients with metastatic disease, 96-month OS rates were similar whether PSA ≤0.2ng/mL was achieved at 6 weeks (47.9%), 12 weeks (50.2%), or 24 weeks (50.3%).² A similar pattern was observed in patients with nonmetastatic disease, with corresponding 96-month OS rates of 77.3%, 75.7%, and 78.0%, respectively.² Conversely, increasing PSA levels at 24 weeks were associated with progressively poorer outcomes.² In patients with metastatic disease, higher PSA categories were associated with increased risk of prostate cancer-specific mortality, with adjusted hazard ratios of 1.70 for PSA >0.2-1.0ng/mL, 2.72 for PSA >1.0-3.0ng/mL, and 4.72 for PSA >3.0ng/mL when compared with PSA ≤0.2ng/mL.² Similar associations were observed among patients with nonmetastatic disease.²

Notably, disease burden continued to influence long-term survival outcomes even among patients who achieved deep PSA responses.² Patients with low-volume metastatic disease were more likely to achieve PSA ≤0.2ng/mL at 24 weeks than those with high-volume metastatic disease (39.9% vs. 22.6%).² Among patients who achieved PSA ≤0.2ng/mL at 24 weeks, 96-month OS was 57.1% in those with low-volume metastatic disease vs. 39.8% in those with high-volume disease.² Similarly, among patients with nonmetastatic disease and PSA ≤0.2ng/mL, 96-month OS was 80.3% in node-negative disease and 73.9% in node-positive disease.²

Treatment-specific analyses further suggested particularly favorable outcomes among patients receiving abiraterone-based therapy, although disease burden remained an important determinant of long-term survival.² Among patients treated with abiraterone ± enzalutamide who achieved PSA ≤0.2ng/mL at 24 weeks, 96-month OS was 82.8% in those with nonmetastatic node-negative disease and 79.4% in those with node-positive disease.² In metastatic disease, corresponding survival rates were 64.1% in patients with low-volume disease and 44.6% in those with high-volume disease.²

In conclusion, the post hoc analysis demonstrated that achieving an on-treatment PSA level of ≤0.2ng/mL at any assessed time point is strongly associated with improved long-term survival.² However, PSA response alone may not fully capture prognosis, and disease burden, including metastatic volume and nodal status, continues to influence survival outcomes even among patients achieving deep PSA responses.² These findings support the integration of on-treatment PSA measurements with baseline disease characteristics and imaging-defined disease burden to refine prognostic assessment and may inform future treatment selection and clinical trial strategies.²